Sprague-Dawley rats treated with a thiamine-deficient (TD) diet develop a syndrome that behaviorally and neuropathologically resembles Wernicke's encephalopathy (the acute phase of Korsakoff's psychosis). Rats exhibiting the syndrome of TD improve behaviorally within hours after intraperitioneal injection of thiamine; after 2-3 months, they weigh the same and appear no different from control animals. Recovered animals of both sexes (at least 6 months post-TD) are significantly less sensitive to the effects of ethanol as measured by behavioral impairment and hypothermia, perhaps due to increased alcohol metabolism and/or reduced CNS sensitivity. Therefore, TD may contribute to both the pharmacokinetic and pharmacodynamic tolerance to alcohol observed in chronic alcoholics. Preliminary findings suggest that a similar phenomenon may be operative in rats made thiamine-deficient in utero. Since the duraction of time required to develop the syndrome of TD varies greatly in outbred strains, we evaluated 10 inbred rat strains to determine their sensitivities to TD. A TD-sensitive strain (M520) and a TD-resistant strain (F344) were selected for further study. M520 rats metabolized ethanol more rapidly, were less impaired at equivalent blood ethanol levels (BEC), and preferred and drank 10-15 times more ethanol in a free-choice (ethanol solution/water) paradigm than F344 rats. Catalase activity was greater in M520 rats, but liver alcohol dehydrogenase (ADH) activities were not significantly different. After 7 weeks of TD, M520 rats showed a greater reduction of baseline body temperature and peak BEC than control rats of the same strain. Both strains showed a twofold increase in liver ADH during TD, but no significant change in catalase, compared with control rats of the same strain.